tbuckley/cabot-search huggingface dataset:
Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia
Authors: Nathaniel D. Anderson, Jack Birch, Theo Accogli, Ignacio Criado, Eleonora Khabirova, Conor Parks, Yvette Wood, Matthew D. Young, Tarryn Porter, Rachel Richardson, Sarah J. Albon, Bilyana Popova, Andre Lopes, Robert Wynn, Rachael Hough, Satyen H. Gohil, Martin Pule, Persis J. Amrolia, Sam Behjati, Sara Ghorashian
Journal: Nature Medicine (2023)

Abstract In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.
Improving access to oral pre-exposure prophylaxis for HIV among international migrant populations
Authors: Warittha Tieosapjaroen, Ying Zhang, Christopher K Fairley, Lei Zhang, Eric P F Chow, Tiffany R Phillips, Heather-Marie Schmidt, Benjamin R Bavinton, Darryl O'Donnell, Limin Mao, Andrew Grulich, Jason J Ong
Journal: The Lancet Public Health (2023)

Pre-exposure prophylaxis (PrEP) is recommended for people susceptible to HIV acquisition, and the scale-up of PrEP programmes has contributed to new HIV case reductions at a population level. However, international migrants continue to be disproportionately affected by HIV. Understanding barriers and facilitators to PrEP implementation among international migrants can optimise PrEP use among this population and ultimately reduce HIV incidence worldwide. We reviewed the evidence regarding factors influencing PrEP implementation among international migrants; 19 studies were included. The barriers and facilitators at the individual level were related to knowledge and risk perception of HIV. Cost, provider discriminations, and health system navigation influenced PrEP use at the service level. Positive or negative perception towards LGBT+ identities, HIV, and PrEP users affected PrEP use at the societal level. Most existing PrEP campaigns do not target international migrants; therefore, culturally tailored approaches for people from different backgrounds are warranted. Potentially migration-related and HIV-related discriminatory policies must be reviewed to increase access to HIV prevention services to end HIV transmission at a population level.
Personalised electronic health programme for recovery after major abdominal surgery: a multicentre, single-blind, randomised, placebo-controlled trial
Authors: Chantal M den Bakker, Frederieke G Schaafsma, Esther C J Consten, Steven E Schraffordt Koops, Eva van der Meij, Peter M van de Ven, Hendrik J Bonjer, Judith A F Huirne, Johannes R Anema
Journal: The Lancet Digital Health (2023)

<h2>Summary</h2><h3>Background</h3> Despite the adoption of minimally invasive techniques, recovery after abdominal surgery takes a long time. Electronic health (eHealth) modalities can provide guidance to patients, facilitating early return to normal activities. We aimed to assess the impact of a personalised eHealth programme on patients' return to normal activities after major abdominal surgery. <h3>Methods</h3> This single-blind, randomised, placebo-controlled trial was done at 11 teaching hospitals in the Netherlands. Eligible participants were aged 18–75 years who underwent a laparoscopic or open colectomy or hysterectomy. An independent researcher randomly allocated participants (in a 1:1 ratio) to either the intervention or control group by use of computer-based randomisation lists, with stratification by sex, type of surgery, and hospital. Participants in the intervention group had access to a perioperative, personalised eHealth programme consisting of both standard face-to-face care and eHealth, that comprised interactive tools offering goal attainment and a personalised outcome measurement, which managed recovery expectations and provided postoperative guidance tailored to each patient. Patients were provided with an activity tracker and had access to a website and mobile app with an electronic consultation (eConsult) functionality. The control group received standard care and access to a placebo website containing recovery advice provided by the hospital. The primary outcome was the number of days between surgery and personalised return to normal activities, assessed with Kaplan-Meier curves. Intention-to-treat and per-protocol analyses were done with a Cox regression model. This trial is registered with the Netherlands National Trial Register (NTR5686). <h3>Findings</h3> Between Feb 11, 2016, and Aug 9, 2017, 355 participants were randomly assigned to the intervention (n=178) or control (n=177) groups. 342 participants were included in the intention-to-treat analysis. The median time until return to normal activities was 52 days (IQR 33–111) in the intervention group, and 65 days (39–152) in the control group (adjusted hazard ratio 1·30 [95% CI 1·03–1·64]; p=0·027). The frequency of postoperative complications did not differ between groups. <h3>Interpretation</h3> This eHealth programme, delivering personalised care based on goal attainment scaling, enabled patients to return to their normal activities 13 days earlier than those who received standard care. <h3>Funding</h3> ZonMw.
Author correction to ‘Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo’ [Acta Pharmaceutica Sinica B 11 (2021) 3950–3965]
Authors: Linglong Deng, Hannah Petrek, Mei-Juan Tu, Neelu Batra, Ai-Xi Yu, Ai-Ming Yu
Journal: Acta Pharmaceutica Sinica B (2023)

[This corrects the article DOI: 10.1016/j.apsb.2021.07.027.].
Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis
Authors: Chao Li, Qiu-ying Ma, Xue-qi Liu, Hai-di Li, Ming-jun Yu, Shuai-shuai Xie, Wen-xian Ma, Ying Chen, Jia-nan Wang, Ruo-bing He, He-ge Bian, Yuan He, Li Gao, Sheng-song Deng, Hong-mei Zang, Qian Gong, Jia-gen Wen, Ming-ming Liu, Chen Yang, Hai-yong Chen, Jun Li, Hui-yao Lan, Juan Jin, Ri-sheng Yao, Xiao-ming Meng
Journal: Molecular Therapy (2023)
Primary Whole-gland Ablation for the Treatment of Clinically Localized Prostate Cancer: A Focal Therapy Society Best Practice Statement
Authors: Sriram Deivasigamani, Srinath Kotamarti, Ardeshir R. Rastinehad, Rafael Sanchez Salas, J.J.M.C.H. de la Rosette, Herbert Lepor, Peter Pinto, Hashim U. Ahmed, Inderbir Gill, Laurence Klotz, Samir S. Taneja, Mark Emberton, Nathan Lawrentschuk, James Wysock, John F. Feller, Sebastien Crouzet, Praveen Kumar M., Denis Seguier, Eric S. Adams, Zoe Michael, Andre Abreu, Kae Jack Tay, John F. Ward, Katsuto Shinohara, Aaron E. Katz, Arnauld Villers, Joseph L. Chin, Phillip D. Stricker, Eduard Baco, Petr Macek, Ardalan E. Ahmad, Peter K.F. Chiu, E. David Crawford, Craig G. Rogers, Jurgen J. Futterer, Soroush Rais-Bahrami, Cary N. Robertson, Boris Hadaschik, Giancarlo Marra, Massimo Valerio, Kian Tai Chong, Veeru Kasivisvanathan, Wei Phin Tan, Derek Lomas, Jochen Walz, Gustavo Cardoso Guimaraes, Nikos I. Mertziotis, Ezequiel Becher, Antonio Finelli, Ali Kasraeian, Amir H. Lebastchi, Anup Vora, Mark A. Rosen, Baris Bakir, Rohit Arcot, Samuel Yee, Christopher Netsch, Xiaosong Meng, Theo M. de Reijke, Yu Guang Tan, Stefano Regusci, Tavya G.R. Benjamin, Ruben Olivares, Mohamed Noureldin, Fernando J. Bianco, Arjun Sivaraman, Fernando J. Kim, Robert W. Given, Shawn Dason, Tyler J. Sheetz, Sunao Shoji, Ariel Schulman, Peter Royce, Taimur T. Shah, Stephen Scionti, Georg Salomon, Pilar Laguna, Rafael Tourinho-Barbosa, Alireza Aminsharifi, Xavier Cathelineau, Paolo Gontero, Armando Stabile, Jeremy Grummet, Leila Ledbetter, Margaret Graton, J. Stephen Jones, Thomas J. Polascik
Journal: European Urology (2023)
Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia
Authors: Anthony R. Mato, Jennifer A. Woyach, Jennifer R. Brown, Paolo Ghia, Krish Patel, Toby A. Eyre, Talha Munir, Ewa Lech-Maranda, Nicole Lamanna, Constantine S. Tam, Nirav N. Shah, Catherine C. Coombs, Chaitra S. Ujjani, Bita Fakhri, Chan Y. Cheah, Manish R. Patel, Alvaro J. Alencar, Jonathon B. Cohen, James N. Gerson, Ian W. Flinn, Shuo Ma, Deepa Jagadeesh, Joanna M. Rhodes, Francisco Hernandez-Ilizaliturri, Pier L. Zinzani, John F. Seymour, Minna Balbas, Binoj Nair, Paolo Abada, Chunxiao Wang, Amy S. Ruppert, Denise Wang, Donald E. Tsai, William G. Wierda, Wojciech Jurczak
Journal: New England Journal of Medicine (2023)

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. We conducted a phase 1–2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.)
A novel ARPKD mouse model with near-complete deletion of the Polycystic Kidney and Hepatic Disease 1 (Pkhd1) genomic locus presents with multiple phenotypes but not renal cysts
Authors: Yu Ishimoto, Luis F. Menezes, Fang Zhou, Teruhiko Yoshida, Taishi Komori, Jiahe Qiu, Marian F. Young, Huiyan Lu, Svetlana Potapova, Patricia Outeda, Terry Watnick, Gregory G. Germino
Journal: Kidney International (2023)
Total neoadjuvant therapy with or without aflibercept in rectal cancer: 3-year results of GEMCAD-1402
Authors: David Pesántez, Sanne ten Hoorn, Isidro Machado, Xabier García-Albéniz, Nuria Rodríguez-Salas, Victoria Heredia-Soto, David Viñal, Carles Pericay, Rocio García-Carbonero, Ferran Losa, Vicente Alonso, Ruth Vera, Jaime Feliu Batlle, Javier Gallego, Antonieta Salud, Miquel Nogué, Laura Layos, Clara Montagut, Jaume Capdevila, Louis Vermeulen, Joan Maurel, Carlos Fernandez-Martos
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC). Methods Patients with magnetic resonance imaging–defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes. Results mF+A and mF had 3-year DFS of 75.2% (95% confidence interval [CI] = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively. Conclusion Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment.
Has the time come to assess small-molecule/biologic drug combinations for the management of moderate-to-severe hidradenitis suppurativa?
Authors: Carlo Alberto Maronese, John R Ingram, Angelo V Marzano
Journal: British Journal of Dermatology (2023)

As the landscape for hidradenitis suppurativa (HS) medical treatment is rapidly expanding, seemingly taking the same steps that marked the evolution of psoriasis management, upcoming agents still do not appear to offer complete disease control. Better control of severe cases of HS refractory to biologic monotherapy may require investigation of pathogenesis-driven, combination regimens sooner rather than later.
Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s disease
Authors: Yun Ju Sung, Chengran Yang, Joanne Norton, Matt Johnson, Anne Fagan, Randall J. Bateman, Richard J. Perrin, John C. Morris, Martin R. Farlow, Jasmeer P. Chhatwal, Peter R. Schofield, Helena Chui, Fengxian Wang, Brenna Novotny, Abdallah Eteleeb, Celeste Karch, Suzanne E. Schindler, Herve Rhinn, Erik C. B. Johnson, Hamilton Se-Hwee Oh, Jarod Evert Rutledge, Eric B. Dammer, Nicholas T. Seyfried, Tony Wyss-Coray, Oscar Harari, Carlos Cruchaga
Journal: Science Translational Medicine (2023)

Proteomic studies for Alzheimer’s disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson’s disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.
Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort
Authors: Georgios Tzimas, Gaurav S. Gulsin, Russell J. Everett, Mariama Akodad, David Meier, Kavishka Sewnarain, Zain Ally, Rawan Alnamasy, Nicholas Ng, Sarah Mullen, David Rotzinger, Janarthanan Sathananthan, Stephanie L. Sellers, Philipp Blanke, Jonathon A. Leipsic
Journal: JACC. Cardiovascular imaging (2023)

With growing adoption of coronary computed tomographic angiography (CTA), there is increasing evidence for and interest in the prognostic importance of atherosclerotic plaque volume. Manual tools for plaque segmentation are cumbersome, and their routine implementation in clinical practice is limited. The aim of this study was to develop nomographic quantitative plaque values from a large consecutive multicenter cohort using coronary CTA. Quantitative assessment of total atherosclerotic plaque and plaque subtype volumes was performed in patients undergoing clinically indicated coronary CTA, using an Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis tool. A total of 11,808 patients were included in the analysis; their mean age was 62.7 ± 12.2 years, and 5,423 (45.9%) were women. The median total plaque volume was 223 mm3 (IQR: 29-614 mm3) and was significantly higher in male participants (360 mm3; IQR: 78-805 mm3) compared with female participants (108 mm3; IQR: 10-388 mm3) (P < 0.0001). Total plaque increased with age in both male and female patients. Younger patients exhibited a higher prevalence of noncalcified plaque. The distribution of total plaque volume and its components was reported in every decile by age group and sex. The authors developed pragmatic age- and sex-stratified percentile nomograms for atherosclerotic plaque measures using findings from coronary CTA. The impact of age and sex on total plaque and its components should be considered in the risk-benefit analysis when treating patients. Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis work flows could provide context to better interpret coronary computed tomographic angiographic measures and could be integrated into clinical decision making.
Measuring anti-islet autoimmunity in mouse and human by profiling peripheral blood antigen-specific CD4 T cells
Authors: Siddhartha Sharma, Xuqian Tan, Josh Boyer, Don Clarke, Anne Costanzo, Brian Abe, Lisa Kain, Marie Holt, Adrienne Armstrong, Marynette Rihanek, Andrew Su, Cate Speake, Peter Gottlieb, Michael Gottschalk, Jeremy Pettus, Luc Teyton
Journal: Science Translational Medicine (2023)

The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell-dependent disease. Here, peptide-major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and humans. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish the absence of autoimmunity versus disease progression. Activated anti-insulin CD4 T cell were detected not only at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen-specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the preclinical phase of anti-islet autoimmunity.
Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma
Authors: Alyssa C. Flint, Dana K. Mitchell, Steven P. Angus, Abbi E. Smith, Waylan Bessler, Li Jiang, Henry Mang, Xiaohong Li, Qingbo Lu, Brooke Rodriguez, George E. Sandusky, Andi R. Masters, Chi Zhang, Pengtao Dang, Jenna Koenig, Gary L. Johnson, Weihua Shen, Jiangang Liu, Amit Aggarwal, Gregory P. Donoho, Melinda D. Willard, Shripad V. Bhagwat, D. Wade Clapp, Steven D. Rhodes
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.